Visfatin as a modulator of factors involved in human placental invasion and angiogenesis: interactions with folic acid and aspirin

CONTEXT: Our previous studies demonstrated the expression of visfatin in the human placenta and its impact on placental cell proliferation and apoptosis. AIMS: This study aimed to examine the effect of visfatin, folic acid (FA), and aspirin (ASA) on markers of invasion and angiogenesis in the human placenta. METHODS: JEG-3 cells and placental villi from normal pregnancies at term were treated for 48 h with visfatin (1 ng/mL, 10 ng/mL or 100 ng/mL) to assess the levels of metalloproteinases (MMP-2/MMP-9), their inhibitors (TIMP-1/TIMP-2), and vascular endothelial growth factors (VEGFA/PLGF). Next, using a pharmacological inhibitor of both the insulin receptor (INSR) and selected kinase pathways, the action of visfatin on the levels of MMPs, TIMPs, VEGFA, and PLGF was analyzed in JEG-3 cells. Finally, using the same research model, the effects of FA (2 nM, 20 nM, 100 nM) or ASA (0.1 mM) on visfatin and INSR expression, as well as the levels of the mentioned factors regulating invasion and angiogenesis, were studied. KEY RESULTS: Visfatin increased MMP-9 levels, while decreasing MMP-2, TIMPs, VEGFA, and PLGF, through distinct intracellular pathways. FA reduced visfatin level and modulated INSR, while ASA decreased both. Moreover, the combined use of FA or ASA with visfatin altered the effect observed for visfatin alone. CONCLUSIONS: Visfatin acts as a novel regulator of invasion factors and decreases the levels of agents involved in angiogenesis. Folic acid or aspirin can modulate its activity. IMPLICATIONS: The regulatory potential of FA and ASA on visfatin action may be relevant in the context of pregnancy-related pathologies.